CN108546266A - A kind of synthetic method of 1,4,6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids - Google Patents
A kind of synthetic method of 1,4,6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids Download PDFInfo
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- CN108546266A CN108546266A CN201810828667.9A CN201810828667A CN108546266A CN 108546266 A CN108546266 A CN 108546266A CN 201810828667 A CN201810828667 A CN 201810828667A CN 108546266 A CN108546266 A CN 108546266A
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- 0 CC*(C(F)(F)F)OC1=C(C)COCC1 Chemical compound CC*(C(F)(F)F)OC1=C(C)COCC1 0.000 description 4
- NIQZAUPMNUPTMP-UHFFFAOYSA-N CCOC(c1n[nH]c2c1COCC2)=O Chemical compound CCOC(c1n[nH]c2c1COCC2)=O NIQZAUPMNUPTMP-UHFFFAOYSA-N 0.000 description 1
- JWRIVWHXPKEJAI-UHFFFAOYSA-N CCOC(c1n[nH]c2c1COCC2)=[U] Chemical compound CCOC(c1n[nH]c2c1COCC2)=[U] JWRIVWHXPKEJAI-UHFFFAOYSA-N 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N O=C1CCOCC1 Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- LWXNHFZBFJMHGU-UHFFFAOYSA-N OC(c1n[nH]c2c1CCCC2)=O Chemical compound OC(c1n[nH]c2c1CCCC2)=O LWXNHFZBFJMHGU-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
The invention discloses a kind of synthetic methods of 3 carboxylic acid of 1,4,6,7 oxinanes [4,3 C] pyrazoles.This method is：Using diethy-aceto oxalate and tetrahydro pyrone as raw material, 2 oxo 2 (4 oxo tetrahydrochysene 2H pyrans, 3 base) ethyl acetate (2) are obtained；Again 1,4,6,7 oxinane o [4,3 c] pyrazoles, 3 carboxylic acid, ethyl ester (3) is generated with hydrazine hydrate cyclization；Last hydrolysis obtains 1,4,6,7 oxinane of target product [4,3 C] pyrazoles, 3 carboxylic acid (4).The present invention solves the problems, such as that raw material is expensive low with yield in the prior art.The route reaction condition is mild, and purifying is simple, and final product is made with higher yield and high-purity, is suitble to technique amplification.
Description
Technical field
The present invention relates to organic chemical industry's intermediate synthesis technical fields, and in particular to a kind of Isosorbide-5-Nitrae, 6,7- oxinanes [4,
3-C] pyrazoles -3- carboxylic acids synthetic method.
Background technology
Isosorbide-5-Nitrae, 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids are a kind of 3,4,5- substituted pyrazolecarboxylic class compounds, are a kind of
Extremely important pharmaceutical intermediate, has a extensive future.The intermediate and its derivative are used as building numerous pharmaceutical drug substances work
Property molecule.Such as prepare a variety of NIK inhibitor, CFTR inhibitor, RBP4 antagonists or kinases inhibitor etc..
There are mainly two types of methods for synthesis 1,4,6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids at present：
1. being prepared by raw material of ethyl diazoacetate
The method under nafoxidine catalysis, is generated using tetrahydrochysene -2H- pyrans -3- ketone and ethyl diazoacetate as raw material
1,4,6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids.The yield of first step reaction is in 50-80%.But ethyl diazoacetate
It is explosive material, easy slug in reaction process is relatively hazardous.During laboratory uses this method, feed intake author 10 grams of scales, can
The yield in document is obtained, but when being amplified to 50 grams of scales, slug occurs and material degenerates completely, illustrates the reproduction of this method
Property difference and amplify when there are prodigious security risks.Raw material tetrahydrochysene -2H- pyrans -3- ketone prices are somewhat expensive simultaneously, are unfavorable for industry
Change and prepares 1,4,6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids.
The synthetic route of another method is：
The method is that 3- bromine tetrahydrochysene -4H- pyrans -4- ketone is raw material, and the Isosorbide-5-Nitrae of low yield, 6,7- tetrahydrochysenes are obtained by three steps
Pyrans [4,3-C] pyrazoles -3- carboxylic acid, ethyl esters.In this method step 3 and when ethyl diazoacetate cyclization, isomers is produced, is led
It causes yield low, is unfavorable for industrialized production.
2. ring-closing condensation reaction occurs as raw material using hydrazine hydrate to prepare
The method is that intermediate 2- oxos -2- (4- oxygen is prepared using tetrahydro pyrone and ethyl oxalyl chloride as raw material
For tetrahydrochysene -2H- pyrans -3- bases) ethyl acetate, then with hydration hydrazine reaction, Isosorbide-5-Nitrae, 6,7- oxinanes [4,3-C] are prepared
Pyrazoles -3- carboxylic acid, ethyl esters.But first step yield only has 19%, and ethyl oxalyl chloride is perishable, it is not easy to maintain.
Therefore, Isosorbide-5-Nitrae is synthesized in the prior art, and there are raw materials to hold high for the method for 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids
The low technical problem of expensive, severe reaction conditions, yield.
Invention content
The object of the present invention is to provide a kind of Isosorbide-5-Nitrae, the synthesis sides of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids
Method, reaction yield is low in the prior art, raw material is expensive, severe reaction conditions, the technological deficiency that should not amplify for solution.
Present invention technical solution used for the above purpose is as follows：
A kind of Isosorbide-5-Nitrae, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids, the synthetic route are as follows：
The specific steps of the synthetic method include：
Step 1. is in tetrahydrofuran solvent, and tetrahydro pyrone (1) and diethy-aceto oxalate are in lithium hexamethyldisilazide
Under effect, 2- oxos -2- (4- oxo tetrahydrochysene -2H- pyrans -3- bases) ethyl acetate (2) is generated in -70~-80 DEG C of reactions；
Aforementioned obtained compound (2) is dissolved in glacial acetic acid step 2. and Isosorbide-5-Nitrae, 6,7- tetrahydrochysenes are obtained by the reaction in hydrazine hydrate
Pyrans o [4,3-c] pyrazoles -3- carboxylic acid, ethyl esters (3).
The aforementioned obtained compound (3) of step 3. is dissolved in ethyl alcohol, and the aqueous solution of lithium hydroxide is slowly dropped into.In 40-
Hydrolysis generates 1,4,6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids (4) at 60 DEG C.
Preferably, the detailed process of the step 1 is：
(a) under protection of argon gas, tetrahydrofuran and lithium hexamethyldisilazide are added in reaction bulb；It is cooled to -70
~-80 DEG C, the mixed solution of the tetrahydrofuran of tetrahydro pyrone (1) and diethy-aceto oxalate is then slowly added dropwise；Drop finishes, heat preservation
It at -70~-80 DEG C, is stirred to react, until the reaction was complete for TLC detections；
(b) -5~10 DEG C are warming up to, water is slowly added dropwise, then pH value is adjusted with concentrated hydrochloric acid；It is extracted with ethyl acetate, saturation food
Salt water washing；Collected organic layer is concentrated under reduced pressure, obtains rufous liquid crude product 2- oxos -2- (4- oxo tetrahydrochysene -2H- pyrans -
3- yls) ethyl acetate (2).
Preferably, the tetrahydro pyrone of step (a) and the molar ratio of lithium hexamethyldisilazide are 1:0.5~1:1.2；
The molar ratio of tetrahydro pyrone and diethy-aceto oxalate is 1:0.5~1:1.2.
Preferably, the reaction time of step (a) is 30min-2h.
Preferably, described in step (b) with concentrated hydrochloric acid adjust pH value range be pH=2~3.
Preferably, step 2 detailed process is：By 2- oxos -2- (4- oxo tetrahydrochysene -2H- pyrans -3- bases) acetic acid second
Ester (2) crude product is added in glacial acetic acid；Hydrazine hydrate is slowly added dropwise at 20-30 DEG C in temperature control；Drop finishes, and at this temperature, is stirred overnight
Reaction；Water and ethyl acetate is added after the reaction was complete in TLC detections；Again pH value is adjusted with solid sodium carbonate；After having adjusted, stirring
30min, layering, aqueous layer with ethyl acetate extraction；Merge all organic layers, then with saturated common salt water washing；It is concentrated under reduced pressure into base
This no liquid flows out, and petroleum ether mashing is added；Filtering, obtains white crude solid Isosorbide-5-Nitrae, 6,7- oxinane o [4,3-c] pyrroles
Azoles -3- carboxylic acid, ethyl esters (3).
Preferably, the solid sodium carbonate adjusts the range of pH value to 8~9.
Preferably, step 3 detailed process is：By crude product 1,4,6,7- oxinanes o [4,3-c] pyrazoles -3- carboxylic acids
Ethyl ester (3) is dissolved in ethyl alcohol；The aqueous solution of lithium hydroxide is slowly added dropwise in 10-20 DEG C of temperature control；Drop finishes, and is warming up to 40-60 DEG C, instead
2-3h is answered, the reaction was complete for TLC detections；After reaction solution is concentrated, then at 10-20 DEG C, pH to 1~2 is adjusted with dilute hydrochloric acid, is had
White solid is precipitated；30min is stirred, filtering is washed with water, and dries, obtains white powder.
In the above synthetic method, three step total recoverys are 65%.Intermediate 2- oxos -2- (4- oxo tetrahydrochysene -2H- pyrans -3-
Base) ethyl acetate (2) and intermediate 1,4,6,7- oxinanes o [4,3-c] pyrazoles -3- carboxylic acid, ethyl esters (3) be all only by letter
Then single post-processing is directly thrown in next step.Final product 1,4,6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids (4) pass through stone
Oily ether mashing, you can obtain sterling, purity reaches 99%.
The present invention also provides synthesis Isosorbide-5-Nitrae, the method for 6,7- oxinane o [4,3-c] pyrazoles -3- carboxylic acid, ethyl esters, synthesis
Route is as follows：
Specific steps include：
Step 1, in tetrahydrofuran solvent, compound 1 and diethy-aceto oxalate under lithium hexamethyldisilazide effect,
Compound 2 is generated in -70~-80 DEG C of reactions；
Step 2, aforementioned obtained compound 2 is dissolved in glacial acetic acid and compound 3 is obtained by the reaction in hydrazine hydrate.Wherein, it walks
Rapid 1 and step 2 specific reaction condition it is as described above.
Compared with prior art, beneficial effects of the present invention are as follows：
1. inventor attempted to prepare by improving catalyst and reaction condition as raw material using ethyl diazoacetate
Target product；As a result, it has been found that the reaction is highly exothermic at room temperature, black smog and slug are generated, reaction condition is more harsh.
Then tetrahydro pyrone is used instead as raw material again, its reaction condition is groped, it is rear to find to use diethy-aceto oxalate and oxinane
Ketone is reacted, and using lithium hexamethyldisilazide as catalyst, can realize under mild reaction conditions compared with
High yield obtains target product.
2. the present invention obtains 2- oxos -2- (4- oxo tetrahydrochysene -2H- pyrroles using diethy-aceto oxalate and tetrahydro pyrone as raw material
Mutter -3- bases) ethyl acetate (2)；Again target product 1,4,6,7- oxinanes [4,3-C] pyrrole is obtained through cyclization and hydrolysis
Azoles -3- carboxylic acids (4).The present invention solves the problems, such as that raw material is expensive low with yield in the prior art.The route reaction condition is mild, behaviour
Make simply, final product is made with higher yield and high-purity.
3. the present invention provides synthesis Isosorbide-5-Nitrae, the route of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids (4) often walks not
Cumbersome column chromatography is needed, simply by simple post-processing, considerably improves yield, total recovery reaches 65% so that should
Synthetic route is suitble to technique amplification.
Specific implementation mode
Illustrate technical scheme of the present invention below by way of specific embodiment.The equal city of raw materials and reagents used in the present invention
Selling can obtain.
Embodiment 1
Under protection of argon gas, in reaction bulb be added tetrahydrofuran (500mL) and lithium hexamethyldisilazide (5L,
5mol,1.0eq.).- 70~-80 DEG C are cooled to, tetrahydro pyrone (1) (500g, 5mol, 1.0eq.) and grass is then slowly added dropwise
The mixed solution (2L) of the tetrahydrofuran of diethyl phthalate (876.8g, 6.0mol, 1.2eq.).Drop finishes, and keeps the temperature at -70~-80 DEG C,
It is stirred to react 30min, the reaction was complete for TLC detections.- 5~10 DEG C are warming up to, water (5L) is slowly added dropwise, then pH is adjusted with concentrated hydrochloric acid
Value.It is extracted with ethyl acetate (2.5L*3), saturated salt solution (2.5L*1) washing.Collected organic layer is concentrated under reduced pressure, obtains reddish brown
Color liquid crude product 2- oxos -2- (4- oxo tetrahydrochysene -2H- pyrans -3- bases) ethyl acetate (2) (1.1kg).
Embodiment 2
2- oxos -2- (4- oxo tetrahydrochysene -2H- pyrans -3- bases) ethyl acetate (2) crude product (1.1kg) is added to ice vinegar
In sour (1.0kg).Hydrazine hydrate (910g, 14.4mol, 2.9eq.) is slowly added dropwise at 20-30 DEG C in temperature control.Drop finishes, in this temperature
Under, it is stirred overnight reaction.Water (10L) and ethyl acetate (5L) is added after the reaction was complete in TLC detections.Again with solid sodium carbonate tune
Save pH value (8~9).After having adjusted, 30min, layering are stirred.Aqueous layer with ethyl acetate (5L*2) extracts.Merge all organic layers, then
It is washed with saturated salt solution (5L).It is concentrated under reduced pressure into basic no liquid outflow, petroleum ether (2L) is added and is beaten.Filtering, obtains white
Color crude solid Isosorbide-5-Nitrae, 6,7- oxinane o [4,3-c] pyrazoles -3- carboxylic acid, ethyl esters (3) (915g, UPLC purity：99%).
Embodiment 3
Crude product 1,4,6,7- oxinanes o [4,3-c] pyrazoles -3- carboxylic acid, ethyl esters (3) (915g) are dissolved in ethyl alcohol (1.8L)
In.The aqueous solution (3.6L) of lithium hydroxide (424g, 11mol, 2.2eq.) is slowly added dropwise in 10-20 DEG C of temperature control.Drop finishes, and is warming up to
50 DEG C, the reaction was complete for reaction 2-3h.TLC detections.After reaction solution is concentrated, then at 10-20 DEG C, with dilute hydrochloric acid adjust pH to
1~2, there is white solid precipitation.30min is stirred, filtering is washed with water (900mL*2), is dried, is obtained white powder 547g, is received
Rate is that 65%, UPLC purity is 99%.
1HNMR (600MHz, DMSO) δ 13.11 (s, 2H), 4.69 (s, 2H), 3.81 (t, J=5.5Hz, 2H), 2.69 (t,
J=5.5Hz, 2H).
m/z(EI):169.0(M+H)+。
The part preferred embodiment of the present invention is above are only, the present invention is not limited in the content of embodiment.For ability
For technical staff in domain, can there is various change and change in the conception range of technical solution of the present invention, made by appoint
What changes and change, within the scope of the present invention.
Claims (8)
1. a kind of Isosorbide-5-Nitrae, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids, which is characterized in that synthetic line is such as
Under,
Specific steps include：
Step 1, in tetrahydrofuran solvent, compound 1 and diethy-aceto oxalate under lithium hexamethyldisilazide effect, in-
70~-80 DEG C of reactions generate compound 2；
Step 2, aforementioned obtained compound 2 is dissolved in glacial acetic acid and compound 3 is obtained by the reaction in hydrazine hydrate；
Step 3, aforementioned obtained compound 3 is dissolved in ethyl alcohol, the aqueous solution of lithium hydroxide is slowly dropped into, at 40-60 DEG C
Hydrolysis generates compound 4.
2. a kind of Isosorbide-5-Nitrae as described in claim 1, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids is special
Sign is that the detailed process of the step 1 is：
(a) under protection of argon gas, tetrahydrofuran and lithium hexamethyldisilazide are added in reaction bulb, is cooled to -70~-80
DEG C, the mixed solution of the tetrahydrofuran of compound 1 and diethy-aceto oxalate is then slowly added dropwise, drop finishes, and keeps the temperature at -70~-80 DEG C,
It is stirred to react, until the reaction was complete for TLC detections；
(b) -5~10 DEG C are warming up to, water is slowly added dropwise, then pH value is adjusted with concentrated hydrochloric acid, is extracted with ethyl acetate, saturated salt solution
Washing, collected organic layer are concentrated under reduced pressure, obtain rufous liquid crude Compound 2.
3. a kind of Isosorbide-5-Nitrae as claimed in claim 2, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids is special
Sign is：The compound 1 of step (a) and the molar ratio of lithium hexamethyldisilazide are 1:0.5~1:1.2, tetrahydro pyrone
Molar ratio with diethy-aceto oxalate is 1:0.5~1:1.2, the reaction time is 30-120min.
4. a kind of Isosorbide-5-Nitrae as claimed in claim 2, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids is special
Sign is：It is pH=2~3 that step (b) concentrated hydrochloric acid, which adjusts the range of pH value,.
5. a kind of Isosorbide-5-Nitrae as described in claim 1, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids is special
Sign is：Step 2 detailed process is：The crude product of compound 2 is added in glacial acetic acid；Temperature control is slowly dripped at 20-30 DEG C
Add hydrazine hydrate；Drop finishes, and at this temperature, is stirred overnight reaction；Water and ethyl acetate is added, then use after the reaction was complete in TLC detections
Solid sodium carbonate adjusts pH value；After having adjusted, 30min, layering, aqueous layer with ethyl acetate extraction are stirred；Merge all organic layers, then
With saturated common salt water washing；It is concentrated under reduced pressure into basic no liquid outflow, petroleum ether mashing is added；It is solid to obtain white crude for filtering
Body compound 3.
6. such as a kind of Isosorbide-5-Nitrae that claim 5 is stated, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids, feature
It is：The solid sodium carbonate adjusts the range of pH value to 8~9.
7. such as a kind of Isosorbide-5-Nitrae that claim 1 is stated, the synthetic method of 6,7- oxinanes [4,3-C] pyrazoles -3- carboxylic acids, feature
It is：Step 3 detailed process is：Crude product 1,4,6,7- oxinanes o [4,3-c] pyrazoles -3- carboxylic acid, ethyl esters (3) are dissolved in
In ethyl alcohol；The aqueous solution of lithium hydroxide is slowly added dropwise in 10-20 DEG C of temperature control；Drop finishes, and is warming up to 40-60 DEG C, reaction 2-3h.TLC inspections
The reaction was complete for survey；After reaction solution is concentrated, then at 10-20 DEG C, pH to 1~2 is adjusted with dilute hydrochloric acid, there is white solid analysis
Go out；30min is stirred, filtering is washed with water, and dries, obtains white powder.
8. a kind of synthesis Isosorbide-5-Nitrae, the method for 6,7- oxinane o [4,3-c] pyrazoles -3- carboxylic acid, ethyl esters, which is characterized in that synthesis road
Line is as follows：
Specific steps include：
Step 1, in tetrahydrofuran solvent, compound 1 and diethy-aceto oxalate under lithium hexamethyldisilazide effect, in-
70~-80 DEG C of reactions generate compound 2；
Step 2, aforementioned obtained compound 2 is dissolved in glacial acetic acid and compound 3 is obtained by the reaction in hydrazine hydrate.
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